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2.
Musculoskeletal Care ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961999

RESUMO

OBJECTIVE: Digital ulcers (DU) remain one of the most burdensome co-morbidities in systemic sclerosis. The objectives of the study were to describe patient-level stratification and to evaluate a nurse-led DU clinic service development. METHODS: A nurse-led digital ulcer clinic was established to identify patients with DU and manage them. Patients were recruited through scleroderma clinics, GP referrals, and self-referrals. The clinic involved patients being treated with appropriate treatment. Patients were stratified according to their DU risk level based on number and severity of ulcers. Among these, 22 patients were asked to complete a patient satisfaction survey. Data were analyzed descriptively. RESULTS: Seventy-five patients were seen in the clinic, 46 (61%) were 56 years of age and above. Patients were identified as high (23%), medium (51%) or low risk (26%) for development of DU. The duration of DU history was from 7 months to 40 years. Prior to attending the nurse-led DU clinic, 90% of patients had received up to six courses of antibiotics for their DU, 76% had attended A&E, and 90% had unscheduled appointments. 90% had been seen by the GP due to DU and subsequently required hospital admissions. During the nurse-led clinic follow-up, only two patients had emergency admission. All patients reported that their needs in personal care of DU were met. CONCLUSION: There are a significant number of people with SSc who have DUs affecting their quality of life as well as needing more healthcare services. A dedicated specialist nurse-led DU clinic may improve overall care of patients.

3.
Arthritis Rheumatol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682743

RESUMO

OBJECTIVE: To describe the associations between autoantibodies, clinical presentation, and outcomes among patients with systemic sclerosis (SSc) in order to develop a novel SSc classification scheme that would incorporate both antibodies and the cutaneous disease subset as criteria. METHODS: Demographic and clinical characteristics, including cutaneous subset, time of disease and organ complication onset, and autoantibody specificities, were determined in a cohort of SSc subjects. Survival analysis was used to assess the effect of the autoantibodies on organ disease and death. RESULTS: The study included 1,325 subjects. Among the antibody/skin disease subsets, anticentromere antibody-positive patients with limited cutaneous SSc (lcSSc) (n = 374) had the highest 20-year survival (65.3%), lowest incidence of clinically significant pulmonary fibrosis (PF) (8.5%) and scleroderma renal crisis (SRC) (0.3%), and lowest incidence of cardiac SSc (4.9%), whereas the frequency of pulmonary hypertension (PH) was similar to the mean value in the SSc cohort overall. The anti-Scl-70+ groups of patients with lcSSc (n = 138) and patients with diffuse cutaneous SSc (dcSSc) (n = 149) had the highest incidence of clinically significant PF (86.1% and 84%, respectively, at 15 years). Anti-Scl-70+ patients with dcSSc had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years. In contrast, in anti-Scl-70+ patients with lcSSc, other complications were rare, and these patients demonstrated the lowest incidence of PH (6.9%) and second highest survival (61.8%) at 20 years. Anti-RNA polymerase antibody-positive SSc patients (n = 147) had the highest incidence of SRC (28.1%) at 20 years. The anti-U3 RNP+ SSc group (n = 56) had the highest incidence of PH (33.8%) and cardiac SSc (13.2%) at 20 years. Among lcSSc patients with other autoantibodies (n = 295), the risk of SRC and cardiac SSc was low at 20 years (2.7% and 2.4%, respectively), while the frequencies of other outcomes were similar to the mean values in the full SSc cohort. Patients with dcSSc who were positive for other autoantibodies (n = 166) had a poor prognosis, demonstrating the second lowest survival (33.6%) and frequent organ complications. CONCLUSION: These findings highlight the importance of autoantibodies, cutaneous subset, and disease duration when assessing morbidity and mortality in patients with SSc. Our novel classification scheme may improve disease monitoring and benefit future clinical trial designs in SSc.

4.
Clin Immunol ; 199: 18-24, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30771500

RESUMO

Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.


Assuntos
Autoanticorpos/sangue , Cinurenina/sangue , RNA Polimerase III/imunologia , Esclerodermia Difusa/metabolismo , Escleroderma Sistêmico/metabolismo , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/imunologia , Escleroderma Sistêmico/imunologia , Triptofano/metabolismo
5.
Eur J Clin Invest ; 49(1): e13032, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30289986

RESUMO

BACKGROUND: Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro-inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear. DESIGN: In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL-17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases. RESULTS: The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis. CONCLUSION: This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases.


Assuntos
Doenças Autoimunes/imunologia , Células Th17/fisiologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/imunologia , Autoimunidade/fisiologia , Diferenciação Celular/imunologia , Estudo de Associação Genômica Ampla , Humanos , Intestinos/imunologia , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , Psoríase/etiologia , Psoríase/imunologia , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/imunologia , Transdução de Sinais/imunologia , Pele/imunologia
6.
Ann Rheum Dis ; 77(9): 1362-1371, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29853453

RESUMO

OBJECTIVES: Skin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFß) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment-the faSScinate study-in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor. METHODS: We analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains. RESULTS: The hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFß-regulated genes and molecular pathways. CONCLUSIONS: We demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases. TRIAL REGISTRATION NUMBER: NCT01532869; Post-results.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Fibroblastos/efeitos dos fármacos , Interleucina-6/imunologia , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Fator de Crescimento Transformador beta/fisiologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Biópsia , Células Cultivadas , Método Duplo-Cego , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica/imunologia , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Receptores de Interleucina-6/antagonistas & inibidores , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Pele/imunologia
7.
Clin Exp Rheumatol ; 36 Suppl 113(4): 50-52, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29465362

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease with a female predominance. The reason for the female predilection in SSc may relate to the difference in hormones between the genders. There are no current data on the influence male-to-female sex transition may have in the development of SSc. We report three patients who developed SSc after initiating the transgender process, and review current literature in regards to transgender patients with connective tissue disease (CTD). METHODS: We describe the clinical features and disease course of three transgender patients who developed SSc after their transition from male-to-female, who presented to our centre. Two additional transgender cases de- scribed in the literature with CTD were included in this review. RESULTS: All three patients developed SSc after having started the hormonal therapy required to transition. Two patients had surgical procedures preceding their diagnosis of SSc. Antibody profile, time of onset and disease features differed among our patients. Hormonal therapies were continued in all patients and they received the standard therapy for SSc. One patient died from complications of her disease. Only two cases describing the development of CTD in transgender patients were identified in the literature and both of these patients were diagnosed with systemic lupus erythematosus (SLE). CONCLUSIONS: This case series suggests that the hormonal modification as part of gender transition may be relevant in development of SSc. No further conclusions can be drawn on the continuation or not of HT.


Assuntos
Hormônios/efeitos adversos , Escleroderma Sistêmico/induzido quimicamente , Procedimentos de Readequação Sexual/efeitos adversos , Pessoas Transgênero , Transexualismo/terapia , Adulto , Estradiol/efeitos adversos , Estrogênios Conjugados (USP)/efeitos adversos , Etinilestradiol/efeitos adversos , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norpregnenos/efeitos adversos , Fatores de Risco , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia , Transexualismo/diagnóstico , Transexualismo/fisiopatologia , Transexualismo/psicologia , Resultado do Tratamento , Pamoato de Triptorrelina/efeitos adversos
8.
Ann Rheum Dis ; 77(4): 563-570, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29306872

RESUMO

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.


Assuntos
Esclerodermia Difusa/diagnóstico , Índice de Gravidade de Doença , Testes Cutâneos/estatística & dados numéricos , Adulto , Área Sob a Curva , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Modelos Logísticos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Polimerase III/análise , Curva ROC , Esclerodermia Difusa/enzimologia , Esclerodermia Difusa/patologia , Pele/patologia
9.
Rheumatology (Oxford) ; 57(2): 370-381, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29207002

RESUMO

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.


Assuntos
Avaliação da Deficiência , Fadiga/fisiopatologia , Dor/fisiopatologia , Esclerodermia Difusa/fisiopatologia , Índice de Gravidade de Doença , Adulto , Efeitos Psicossociais da Doença , Europa (Continente) , Fadiga/etiologia , Feminino , Dedos , Força da Mão , Inquéritos Epidemiológicos , Humanos , Masculino , Dor/etiologia , Estudos Prospectivos , Esclerodermia Difusa/complicações , Úlcera Cutânea/etiologia , Úlcera Cutânea/fisiopatologia
10.
Arthritis Rheumatol ; 70(3): 450-461, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29193892

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) has the highest case-specific mortality of any rheumatic disease, and no effective therapy is available. A clear manifestation of SSc is the presence of autoantibodies. However, the origin of autoantibody-producing B lymphocytes, their mechanisms of activation and autoantibody production, and their role remain unclear. This study was undertaken to identify mechanisms that contribute to pathogenic B cell generation and involvement in SSc and to assess the altered distribution and function of B cells in SSc patients. METHODS: Multicolor flow cytometry was performed to determine B cell subset distribution, cytokine production, and tolerance induction in SSc patients and healthy controls. Cytokine production following stimulation of the cells ex vivo was determined by multiplex assay. RESULTS: A range of defects in B lymphocyte tolerance and cytokine production in SSc were noted. There was evidence of altered distribution of transitional B cell subsets, increased production of interleukin-6 (IL-6) and IL-8, and defective tolerance induction in SSc B cells. In addition, B cells from SSc patients had a reduced ability to produce IL-10 when stimulated through innate immune pathways. In contrast to healthy individuals, tolerance checkpoints in SSc patients failed to suppress the emergence of B cells that produce autoantibodies with specificity to the Scl-70 antigen, which is strongly associated with SSc. These defects were paralleled by altered intracellular signaling and apoptosis following B cell receptor engagement. CONCLUSION: Our findings provide new insights into mechanisms underlying defective B lymphocyte responses in patients with SSc and their contribution to disease.


Assuntos
Linfócitos B/metabolismo , Citocinas/metabolismo , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Autoanticorpos/imunologia , Linfócitos B/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade
11.
Rheumatol Adv Pract ; 2(1): rky002, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31431952

RESUMO

Objectives: The aim was to define clinical characteristics and long-term survival of patients with dcSSc and positive ACA. Methods: We identified all cases of ACA+ SSc in our cohort (n = 1313). Those with dcSSc (ACA+ diffuse) were compared with representative groups of consecutive ACA+ patients with limited subset (ACA+ limited) and ACA- dcSSc (non-ACA diffuse). Results: Thirty-five patients (2.7%) were ACA+ diffuse. The peak modified Rodnan skin score was not significantly different between the dcSSc subgroups, but it occurred later in the disease course in ACA+ diffuse (88.54 vs 30.65 months, P < 0.001). Patterns of organ involvement were different between the groups. ACA+ diffuse had a higher incidence of interstitial lung disease than ACA+ limited (22.86 vs 4.43%, P = 0.001), but lower than non-ACA diffuse (41.18%, P = 0.042). More patients developed pulmonary hypertension in the ACA+ diffuse group (28.5 vs 12.0% ACA+ limited or 12.0% non-ACA diffuse), although this was attributable to the longer follow-up in these patients. The cumulative incidence of pulmonary hypertension was not different from the other two groups. The incidence of cardiac involvement was similar between the dcSSc groups, and scleroderma renal crisis was more frequent in the non-ACA diffuse group. Survival in ACA+ patients was similar in both subsets, whereas non-ACA diffuse had higher mortality. Conclusion: ACA+ dcSSc is uncommon and has a distinct clinical phenotype, with a more insidious onset of skin and organ involvement. Even in dcSSc, ACA appears protective for organ-based complications, namely interstitial lung disease and scleroderma renal crisis, and is associated with a better survival than expected in dcSSc.

12.
J Scleroderma Relat Disord ; 3(3): 249-252, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30705970

RESUMO

The episodic nature of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) has led to a reliance on patient-reported outcome (PRO) instruments such as the Raynaud's Condition Score (RCS) diary. Little is known about the utilisation in routine clinical practice and health professional attitudes towards existing PRO instruments for assessing SSc-RP. Members of the Scleroderma Clinical Trials Consortium Vascular Working Group (SCTC-VWG, n=28) were invited to participate in a survey gauging attitudes towards the RCS diary and the perceived need for novel PRO instruments for assessing SSc-RP. Nineteen SCTC-VWG members (68% response rate) from academic units based in North America (n=9), Europe (n=8), South America (n=1) and Australasia (n=1) took part in the survey. There was broad consensus that RCS diary returns could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of RP, habituation to RP symptoms, evolution of RP symptom characteristics with progressive obliterative microangiopathy, patient coping strategies, respondent burden and placebo effect. There was consensus that limitations of the RCS diary might be a barrier to drug development (79% of respondents agree/strongly agree) and that a novel PRO instrument for assessing SSc-RP should be developed with the input of both clinicians and patients (84% agree/strongly agree). Perceived potential limitations of the RCS diary have been identified along with concerns that such factors might impede drug development programs for SSc-RP. There is support within the systemic sclerosis community for the development of a novel PRO instrument for assessing SSc-RP.

13.
Arthritis Res Ther ; 19(1): 156, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28676069

RESUMO

BACKGROUND: Systemic sclerosis (SSc; scleroderma) is an uncommon autoimmune rheumatic disease characterised by autoimmunity, vasculopathy and fibrosis. Gene expression profiling distinguishes scleroderma from normal skin, and can detect different subsets of disease, with potential to identify prognostic biomarkers of organ involvement or response to therapy. We have performed gene expression profiling in skin samples from patients with limited cutaneous SSc (lcSSc). METHODS: Total RNA was extracted from clinically uninvolved skin biopsies of 15 patients with lcSSc and 8 healthy controls (HC). Gene expression profiling was performed on a DNA oligonucleotide microarray chip. Differentially expressed genes (DEG) were identified using significance analysis of microarrays (SAM). Functional enrichment analysis of gene signatures was done via g:Profiler. RESULTS: There were 218 DEG between lcSSc and HC samples (false discovery rate <10%): 181/218 DEG were upregulated in lcSSc samples. Hierarchical clustering of DEG suggested the presence of two separate groups of lcSSc samples: "limited 1" and "limited 2". The limited-1 group (13 samples, 10 unique patients) showed upregulation of genes involved in cell adhesion, cardiovascular system (CVS) development, extracellular matrix and immune and inflammatory response. The CVS development signature was of particular interest as its genes showed very strong enrichment in response to wounding, response to transforming growth factor (TGF)-ß and kinase cascade. Neither limited-2 samples (six samples, five unique patients) nor HC samples showed functional enrichment. There were no significant differences in demographic or clinical parameters between these two groups. These results were confirmed using a second independent cohort. CONCLUSIONS: Our study suggests the presence of molecular subsets in lcSSc based on gene expression profiling of biopsies from uninvolved skin. This may reflect important differences in pathogenesis within these patient groups. We identify differential expression of a subset of genes that relate to CVS and are enriched in fibrotic signalling. This may shed light on mechanisms of vascular disease in SSc. The enrichment in profibrotic profile suggests that dysregulated gene expression may contribute to vasculopathy and fibrosis in different disease subsets.


Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Perfilação da Expressão Gênica/métodos , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/genética , Pele/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Clin Rev Allergy Immunol ; 53(2): 237-264, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28456914

RESUMO

B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases. Indeed, newly generated B lymphocytes undergo rigorous tolerance mechanisms in the bone marrow and, subsequently, in the periphery after their migration. Furthermore, activation of mature B cells is regulated through controlled expression of co-stimulatory receptors and intracellular signalling thresholds. All these regulatory events determine whether and how B lymphocytes respond to antigens, by undergoing apoptosis or proliferation. However, defects that alter regulated co-stimulatory receptor expression or intracellular signalling thresholds can lead to diseases. For example, autoimmune diseases can result from altered regulation of B cell responses leading to the emergence of high-affinity autoreactive B cells, autoantibody production and tissue damage. The exact cause(s) of defective B cell responses in autoimmune diseases remains unknown. However, there is evidence that defects or mutations in genes that encode individual intracellular signalling proteins lead to autoimmune diseases, thus confirming that defects in intracellular pathways mediate autoimmune diseases. This review provides a synopsis of current knowledge of signalling proteins and pathways that regulate B lymphocyte responses and how defects in these could promote autoimmune diseases. Most of the evidence comes from studies of mouse models of disease and from genetically engineered mice. Some, however, also come from studying B lymphocytes from patients and from genome-wide association studies. Defining proteins and signalling pathways that underpin atypical B cell response in diseases will help in understanding disease mechanisms and provide new therapeutic avenues for precision therapy.


Assuntos
Autoimunidade , Linfócitos B/imunologia , Imunidade Humoral , Imunomodulação , Transdução de Sinais/imunologia , Animais , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
15.
Ann Rheum Dis ; 76(7): 1207-1218, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28188239

RESUMO

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Esclerodermia Difusa/tratamento farmacológico , Adulto , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Estudos de Coortes , Intervenção Médica Precoce , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/imunologia , Estudos Prospectivos , RNA Polimerase III/imunologia , Esclerodermia Difusa/imunologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
17.
Clin Rev Allergy Immunol ; 52(3): 401-423, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27515671

RESUMO

Cyclosporine A, an inhibitor of calcineurin, exerts an immunomodulator action interfering with T cell activation. Even though novel therapeutic tools have emerged, CyA still represents a suitable option in several clinical rheumatology settings. This is the case of refractory nephritis and cytopenias associated with systemic lupus erythematosus. Furthermore, CyA is a valued therapeutic tool in the management of uveitis and thrombophlebitis in course of Behçet's disease. Topical CyA has been proven to be beneficial in the dry eye of Sjogren's syndrome, whereas oral treatment with CyA can be considered for the severe complications of adult onset Still's disease. CyA provides a therapeutic option in psoriatic arthritis, being rather effective in skin disease. CyA is currently regarded as a second-line option for patients with inflammatory myopathies refractory to standard regimen. CyA is used even in paediatric rheumatology, in particular in the management of juvenile dermatomyositis and macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Importantly, CyA has been shown to suppress the replication of HCV, and it can thus be safely prescribed to those patients with chronic hepatitis C. Noteworthy, CyA can be administered throughout the gestation course. Surely, caution should be paid to CyA safety profile, in particular to its nephrotoxicity. Even though most evidence comes from small and uncontrolled studies with few randomised controlled trials, CyA should be still regarded as a valid therapeutic tool in 2016 rheumatology.


Assuntos
Artrite Juvenil/tratamento farmacológico , Síndrome de Behçet/tratamento farmacológico , Ciclosporina/uso terapêutico , Hepacivirus/fisiologia , Hepatite C Crônica/tratamento farmacológico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico , Doença de Still de Início Tardio/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Adulto , Criança , Humanos , Ativação Linfocitária/efeitos dos fármacos , Reumatologia/tendências , Linfócitos T/imunologia , Replicação Viral
18.
Clin Exp Rheumatol ; 35(1): 80-84, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27494156

RESUMO

OBJECTIVES: To review our clinical experience of this rare condition and describe the clinical features and response to therapy in a cohort of patients with erythromelalgia (EM), a rare condition, characterised by paroxysmal hyperthermia of the extremities with erythema, pain and intense burning. METHODS: A review was made of the electronic and paper medical records of patients with the diagnosis of EM, with a telephone interview to verify and complete clinical information relating treatment and outcome. RESULTS: 46 patients (41 females) were included in this study. Mean age was 57 years and mean duration of symptoms was 16 years. Raynaud's phenomenon was present in 36 patients (80%) and 4 patients (9%) had systemic sclerosis. Smoking (current or previous) was identified as a possible risk factor in 26 cases and exposure to chronic vibration in 3 cases. Overall, the effect on quality of life was mild in 15% of cases, moderate in 30% and severe in 48%. The most common symptoms were burning (96%), heat (93%), pain (87%), and redness (83%). Symptoms affected the lower limbs in 98% of cases, upper limbs in 76%, face in 20% and trunk in 11%. Triggers included heat (85%), exercise (78%) and time of day (76%). Various medications were tried, showing poor effect in most cases. Intravenous iloprost was given to 27 patients, with benefit in 17 patients (63%). CONCLUSIONS: Erythromelalgia is a rare chronic debilitating condition. Exercise, heat and night time are common triggers. Current medical therapies are seldom effective and further research is sorely needed.


Assuntos
Eritromelalgia/diagnóstico , Eritromelalgia/tratamento farmacológico , Iloprosta/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Adulto , Eritromelalgia/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Doença de Raynaud/complicações , Fatores de Risco , Fumar , Avaliação de Sintomas , Resultado do Tratamento
19.
Ann Rheum Dis ; 76(1): 270-276, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27621285

RESUMO

BACKGROUND: Validity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised. METHODS: Three investigators assigned an activity score on a 0-10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate-multivariate linear regression analyses were used to define variables predicting the 'gold standard', their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0-10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS). RESULTS: A weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted <70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001). CONCLUSIONS: A preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies.


Assuntos
Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/epidemiologia , Sensibilidade e Especificidade , Adulto Jovem
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